This laboratory has utilized various animal models of metabolic encephalopathy in order to explore their biochemical basis and pathophysiology. In the past, our animal models of encephalopathy have included uremia, thyroid disease, hydrocephalus and pneumococcal meningitis. Most recently major attention has focused on water intoxication in a model of "inappropriate secretion of anti-diuretic hormone" and thiamine deficiency encephalopathy. A major emphasis has been the analysis of brain permeability and membrane transport involving sugars, sodium, potassium, organic acids, and thiamine. We have utilized brain in vivo, brain slices and subcellular preparations of brain in vitro. A major long-term objective is to understand the special regional vulnerability of the brain that characterizes many genetic, toxic and deficiency diseases which affect the brain. The immediate objectives of this application involve: 1) analysis of adaptive mechanisms in brain in response to changes in plasma osmolality; 2) the roles of the thiamine phosphates in brain, with particular reference to thiamine deficiency encephalopathy, and in the hereditary cerebellar ataxia of rabbits.